ABSTRACT
The HIV-1 envelope glycoprotein (Env) trimer is the key target for vaccines aimed at inducing neutralizing antibodies (NAbs) against HIV-1. The clinical candidate immunogen ConM SOSIP.v7 is a stabilized native-like HIV-1 Env trimer based on an artificial consensus sequence of all HIV-1 isolates in group M. In preclinical studies ConM SOSIP.v7 trimers induced strong autologous NAb responses in non-human primates (NHPs). To fine-map these responses, we isolated monoclonal antibodies (mAbs) from six cynomolgus macaques that were immunized three times with ConM SOSIP.v7 protein and boosted twice with the closely related ConSOSL.UFO.664 immunogen. A total of 40 ConM and/or ConS-specific mAbs were isolated, of which 18 were retrieved after the three ConM SOSIP.v7 immunizations and 22 after the two immunizations with ConSOSL.UFO.664. 22 mAbs (55%) neutralized the ConM and/or ConS virus. Cross-neutralization of ConS virus by approximately one-third of the mAbs was seen prior to ConSOSL.UFO.664 immunization, albeit with modest potency. Neutralizing antibodies predominantly targeted the V1 and V2 regions of the immunogens, with an apparent extension towards the V3 region. Thus, the V1V2V3 region is immunodominant in the potent NAb response elicited by two consensus sequence native-like HIV-1 Env immunogens. Immunization with these soluble consensus Env proteins also elicited non-neutralizing mAbs targeting the trimer base. These results inform the use and improvement of consensus-based trimer immunogens in combinatorial vaccine strategies.
ABSTRACT
One year into the Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), effective treatments are still needed 1-3 . Monoclonal antibodies, given alone or as part of a therapeutic cocktail, have shown promising results in patients, raising the hope that they could play an important role in preventing clinical deterioration in severely ill or in exposed, high risk individuals 4-6 . Here, we evaluated the prophylactic and therapeutic effect of COVA1-18 in vivo , a neutralizing antibody isolated from a convalescent patient 7 and highly potent against the B.1.1.7. isolate 8,9 . In both prophylactic and therapeutic settings, SARS-CoV-2 remained undetectable in the lungs of COVA1-18 treated hACE2 mice. Therapeutic treatment also caused a dramatic reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg - 1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 had a very strong antiviral activity in the upper respiratory compartments with an estimated reduction in viral infectivity of more than 95%, and prevented lymphopenia and extensive lung lesions. Modelling and experimental findings demonstrate that COVA1-18 has a strong antiviral activity in three different preclinical models and could be a valuable candidate for further clinical evaluation.
ABSTRACT
AIM: Large (> 2 cm) rectal adenomas are currently treated by transanal endoscopic microsurgery (TEM) or piecemeal endoscopic mucosal resection (EMR). The potential lower morbidity of EMR becomes irrelevant if it is less effective. We aimed to compare the safety and effectiveness of EMR and TEM for large rectal adenomas. METHOD: Data from patients undergoing TEM or EMR for a rectal adenoma > 2 cm in eight hospitals were retrospectively collected. Patient- and procedure-related characteristics, complications and recurrences were recorded. As EMR may require several attempts to achieve complete resection, early (after a single intervention) and late (permitting re-treatment for residual adenoma within 6 months) recurrence rates were determined. RESULTS: Two hundred and ninety-two (292) patients (49% male; mean age 67 years) were included; 219 were treated by TEM and 73 by EMR. Adenomas treated by EMR were smaller (median 30 vs 40 mm; P = 0.007). Perioperative complication rates were 2% for TEM and 6% for EMR (P = 0.171). Postoperative complications occurred in 24% of TEM patients and in 13% of EMR patients (P = 0.038). Median hospitalization after TEM was 3 days vs 0 days after EMR (P < 0.001). Median follow-up was 12.6 months (0-47 months); Early recurrence rates were 10.2% in TEM patients and 31.0% in EMR patients (P < 0.001); late recurrence rates were 9.6% and 13.8%, respectively (P = 0.386). CONCLUSION: After a single intervention, EMR of large rectal adenomas seems less effective, but safer than TEM. When allowing re-treatment of residual adenoma within 6 months, EMR and TEM seem equally effective. A prospective randomized comparison seems to be necessary.
